Search

A highly efficient synthesis of the potent and selective NK-1 receptor antagonist is described. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented [S.sub.N]2 reaction pathway under typical [S.sub.N]1 reaction conditions.

An efficient five-step synthesis of 1,6-naphthyridone (3b), a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9.

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-alpha]pyrimidin-7-yl]-propan-2-ol, an oral GABA(sub A) alpha2/3-selective agonist is described. Consecutive Pd-catalyzed coupling steps to assemble the final free base in high yield and regioselectivity highlight the synthesis.

Research has been conducted on the 1,2,3-trisubstituted cyclohexanes and cyclopentanes. The results of the asymmetric synthesis of these compounds developed for the preparation of the 2,3-disubstituted cyclohexenones and cyclopentenones are presented.

Research has been conducted on (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)-cyclopentanone. The results of the asymmetric synthesis of this compound are presented.

Results demonstrate that annulation of stabilized ketones and esters leads to the formation of pyridines and pyridones in good yields. The annulation reaction requires vinamidinium hexafluorophosphate salts and the reactions occur via the dienaminone formation.

The synthesis of substituted trimethinium salts is described. Acid reduction of 2-chlorovinamidinium salts yields vinamidinium salts. The reaction using substituted acetic acids and formamides in the presence of phosphorous oxychloride gives the vinamidinium hexafluorophosphate salts.

The reisolation of breynins A and B leads to the assignment of their complete structures and a study of their oxidative conversion from A to B preparatory their total synthesis. The breynins, first isolated in 1973, are orally active hypocholesterolemic agents. Their structures consist of three pyranose units O-linked to one another and to a breynogenin aglycon bearing a hydrobenzoate unit as a C11 ester. Their full spectroscopic characterization is made possible by the preparation of breynin undecaacetate. The analysis confirms the breynin A structure reported by Ohkuma et al, but revises the structure of breynin B as a sulfoxide rather than a hemithioacetal.

Suzuki coupling is used for showing that various dihaloazoles are monoarylated at a single C-X bond with high selectivity. The selectivity is switched for some dihaloazoles by changing the palladium catalyst and these conditions are used for coupling of a variety of aryl-, heteroaryl-, cyclopropyl- and vinylboronic acids with high selectivities.

A general approach is developed for preparing 3,5-diarylcyclopentenones, where the key aspects have included the intramolecular Friedel-Crafts-type cyclization of vinyl chlorides and subsequent Pd-catalyzed cross-coupled reactions. The vinyl chloride-bearing arylacetic acid precursors are available by straightforward alkylation of arylacetic acid esters and have undergone cyclization to produce 3-chloro-5-aryl-2-cyclopentenones when treated with Al[Cl.sub.3].

Microscale parallel experimentation is used for discovering three catalyst systems capable of coupling secondary organotrifluororates with sterically and electronically demanding aryl chlorides and bromides. A ligand-dependent [beta]-hydride elimination/reinsertion mechanism is implicated in the cross-coupling process, which has led to isomeric mixtures of coupled products.

A convergent strategy involving [S.sub.N]Ar coupling of activated aryl fluoride with hydroxypyridine was used to synthesize glucokinase activator. The method involved (-)-sparteine-mediated enantioselective Pd-catalyzed [alpha]-arylation of N-Boc-pyrrolidine followed by in situ transmetalation to zinc.

An efficient process is described for the preparation of [gamma]-secretase inhibitor. The operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer, which is based on a reversible carbon-sulfur bond formation under acidic conditions.

The method to cycloacylate aniline derivatives to 4-quinolones in the presence of Eaton's reagent which also be used to prepare host of heterocycles and bis-quinolones is described.

A general, enantioselective, palladium-catalyzed arylation of N-Boc-pyrrolidine that proceeds via in situ generated 2-pyrrolidinozinc reagent is reported. This sequence has offered a number of advantages over existing methods and has represented the most convenient and practical synthesis of enantiomerically enriched 2-arylpyrrolidines and 2,5-diarylpyrrolidines.

A wide variety of benzo[b]furans were synthesized efficiently in a study via a CuI-catalyzed ring closure of 2-haloaromatic ketones. Many structurally interesting benzo[b]furans were readily prepared in a catalytic manner in good to excellent yields.

A practical preparation of an alpha(sub v)beta(sub 3) antagonist is reported. The antagonist consists of three key components that were prepared in various methods, due to which a highly convergent process for the drug candidate was defined.

A synthesis of nitro anilines and formyl that should lend itself to synthetic application is described. The reaction emphasizes that substituted aromatics are easily accessible via de novo synthesis rather than the use of conventional electrophilic substitution.

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47 percent overall yields is described. With the use of pyridinylthioimidate 27 in the presence of ZnCl2, the problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 could be overcome.

Research has been conducted on substituted 1,8-naphthyridin-4-one analogues. The authors describe the procedure developed for the preparation of these compounds.

An efficient stereoselective synthesis of the orally active NK(sub 1) receptor antagonist Aprepitant is described. A novel crystallization-induced diastereoselective glycosidation as well as an unprecented stereoselective one-pot transformation of an 1,4-oxazin-3-one into a 3-(4-fluorophenyl) morpholine derivative serve as the foundation of this practical and exceedingly efficient approach.

Research has been conducted on 2-substituted quinolines, 1,8-naphthyridines and chromone derivatives. The evaluation of catalysts has been carried out during the preparation of these compounds from o-aminoaromatic aldehydes and methyl ketones, and the details are reported.

The (-)-furaquinocin C is prepared in six steps starting from (R)-(+)-angelicalactone. The regioselective synthesis is based on Diels-Alder reaction. The structure of 3 is established by single crystal X-ray analysis. Lactones are obtained as intermediates during the synthetic procedure. Monte carlo simulation of these lactones with MM2 field produces a lowest-energy conformer in which C(7) methylene is anti oriented to methyl, substituted at C(4).

Nuclear Overhauser effect (NOE) measurements help determine the complete relative stereochemistry of pyripyropene A, which is a potent bioavailable inhibitor of Acyl-CoA:cholesterol acyltransferase. Single-crystal X-ray analysis helps determine the relative conformations at C(5) and C(13) and support the NOE results. A modified Mosher NMR method helps elucidate the absolute conformation of pyripyropene A. Common biosynthetic origin of pyripyropenes, suggests similar relative and absolute stereochemistry for congeners B-D.